308060-74-4AlbuminDTXSID1040409NOCASSerumDTXSID204112357-88-5HVYWMOMLDIMFJA-DPAQBDIFSA-NHVYWMOMLDIMFJA-DPAQBDIFSA-N
CholesterolCholest-5-en-3-ol (3beta)-
(-)-Cholesterol
3beta-Hydroxycholest-5-ene
CHLOEST-5-EN-3-OL (3-beta)-
Cholest-5-en-3-ol, (3beta)-
Cholest-5-en-3beta-ol
Cholesterin
Cholesteryl alcohol
colesterol
Lidinit
Lidinite
NSC 8798
Provitamin D
5:6-Cholesten-3beta-ol
DTXSID302240110028-15-6CBENFWSGALASAD-UHFFFAOYSA-NCBENFWSGALASAD-UHFFFAOYSA-N
OzoneAtmospheric ozone
Healozone
Oxygen, mol.
Ozone(16O16O16O)
Triatomic oxygen
DTXSID002109810102-43-9MWUXSHHQAYIFBG-UHFFFAOYSA-NMWUXSHHQAYIFBG-UHFFFAOYSA-N
Nitric oxideNitric oxide (NO)
Amidogen, oxo-
monoxido de nitrogeno
Monoxyde d'azote
Nitric oxide trimer
Nitrogen monooxide
nitrogen monoxide
Nitrogen(II) oxide
Nitrosyl radical
Oxido nitrico
Stickstoffmonoxid
UN 1660
DTXSID1020938NOCASCigarette smokeCS
DTXSID5035038NOCASDiesel engine exhaustDiesel Exhaust
DE
DTXSID1024043VT:0002327respiratory function trait2decreasedAlbumin2017-10-25T08:32:072017-10-25T08:32:07Serum2021-10-27T11:18:402021-10-27T11:18:40Impregnation products2021-10-27T11:19:112021-10-27T11:19:46Meconium2021-10-27T11:21:002021-10-27T11:21:00nanoparticles2016-12-21T09:40:062016-12-21T09:40:06Cholesterol2021-10-27T11:21:482021-10-27T11:21:48Chemical2017-02-07T13:22:422017-02-07T13:22:42Ozone2021-07-21T10:18:562021-09-28T08:26:52Nitric oxide2021-07-22T09:57:382021-07-22T09:57:38Cigarette smoke2021-06-24T07:10:582021-09-28T09:07:54Diesel engine exhaust2021-08-06T08:41:152021-09-28T08:55:47PM102021-07-22T09:54:462021-07-22T09:54:4610090mouseWCS_9606human10116ratReduced tidal volume Reduced tidal volumeOrgan2019-07-03T13:19:412021-02-16T11:55:39Loss of alveolar capillary membrane integrityLoss of alveolar capillary membrane integrityTissue<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The alveolar-capillary membrane (ACM) is the gas exchange surface of the lungs that is only ~0.3µm thick and is the largest surface area within the lung that separates the interior of the body from the environment. It is comprised of the microvascular endothelium, interstitium, and alveolar epithelium. As a consequence of its anatomical position, and the large surface area, it is the first point of contact for any inhaled pathogen, particles or toxic substances. Thus, ACM is subjected to injury constantly and rapidly repaired following the external insults without formation of fibrosis or scar tissue. The extent of ACM injury or how rapidly its integrity is restored is a pivotal determinant of whether the lung restores its normal functioning following an injury or is replaced by fibrotic lesion or scar tissue (Fukuda et al., 1987; Schwarz et al., 2001). Significant loss of endothelium and epithelium of the ACM results in loss of the barrier and membrane integrity. Increased membrane permeability leading to efflux of protein-rich fluid into the peribronchovascular interstitium and the distal airspaces of the lung, disruption of normal fluid transport via downregulated Na<sup>+</sup> channels or malfunctioning Na<sup>+</sup>/K<sup>+</sup>ATPase pumps, loss of surfactant production, increased expression of epithelial or endothelial cell markers such as Intercellular adhesion molecule-1 (ICAM-1) or decreased expression of surfactant protein D (SP-D) are few of the markers of decreasing lung compliance arising from the lost integrity of ACM (Johnson and Matthay, 2010).</span></span></p>
<p><strong><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>Literature evidence for its perturbation:</em></span></span></strong></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Bleomycin exposure causes alveolar barrier dysfunction (Miyoshi et al., 2013). Cigarette smoke impairs tight junction proteins and leads to altered permeability of the epithelial barrier (Schamberger et al., 2014). Exposure to bleomycin destroys the structural architecture of tight junctions, increases permeability, epithelial death and loss of specialised repair proteins such as claudins. Thoracic radiation and bleomycin induced lung injury results in decreased expression of E-cadherin and Aquaporin-5 (AQP5) expression (Almeida et al., 2013; Gabazza et al., 2004).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Repeated exposure to biopersistent toxic substances, pathogens or lung irritants initiate non-resolving inflammation and ACM injury (Costabel et al., 2012). Chronic inflammation mediated by overexpression of cytokines such as Interleukine (IL)-1 (Kolb et al., 2001), Tumor necrosis factor alpha (TNF-</span></span><span style="font-size:11.0pt"><span style="font-family:"Arial",sans-serif">α</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">) (Sime et al., 1998), T helper type 2 cytokine IL-13 or exposure to specific proteinases initiate ACM injury, leading to significant loss of the epithelium and endothelium of the ACM resulting loss of barrier integrity. In patients diagnosed with idiopathic pulmonary fibrosis (IPF), both type 1 pneumocyte & endothelial cell injury with ACM barrier loss is observed. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Bleomycin and silica exposure generate persistent inflammation and lung damage (Chua et al., 2005; Thrall and Scaliso, 1995). Exposure to single-walled carbon nanotubes (SWCNTs) induces persistent inflammation, granuloma formation and diffuse intestinal fibrosis in mice after pharyngeal aspiration (Shvedova <em>et al.,</em> 2005). Multi-walled carbon nanotubes act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer <em>et al.,</em> 2013). Inhaled particles induce chronic inflammation (Ernst <em>et al., </em>2002; Hamilton et al., 2008; Thakur et al., 2008). Increased numbers of alveolar macrophages, neutrophils and eosinophils are observed in the bronchoalveolar lavage fluid (BALF) of patients suffering from IPF and chronic inflammation is associated with decreased survival (Parra <em>et al.</em>, 2007; Schwartz <em>et al.,</em> 1991; Yasuoka <em>et al.,</em> 1985).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The BALF of patients diagnosed with interstitial diseases contains increased levels of 8-isoprostane (Psathakis <em>et al.</em>, 2006) and carbonyl-modified proteins (Lenz et al., 1996), markers of oxidative modification of lipids and proteins. <em>In vivo</em>, increased reactive oxygen species (ROS) levels in rodents (Ghio <em>et al.</em>, 1998) and enzymatic production of nitric oxide in rat alveolar macrophages is observed after asbestos exposure (Quinlan <em>et al.</em>, 1998). Some nanoparticles induce oxidative stress that contributes to cellular toxicity (Shi <em>et al.</em>, 2012). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase derived ROS is a critical determinant of the pulmonary response to SWCNTs in mice (Shvedova <em>et al.</em>, 2008). Oxidative lipidomics analysis of the lungs of carbon nanotube (CNT)-exposed mice showed, phospholipid oxidation (Tyurina <em>et al.</em>, 2011). ROS synthesis is suggested to be important for inflammosome activation involving NLR-related protein 3 complex, activated caspase-1 and IL-1</span></span><span style="font-size:11.0pt"><span style="font-family:"Arial",sans-serif">β</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">, which is observed following exposure to a variety of pro-inflammatory stimuli including, asbestos and crystalline silica (Cassel <em>et al.</em>, 2008; Dostert <em>et al.</em>, 2008) and long needle-like CNTs. In the case of asbestos, frustrated phagocytosis triggered ROS synthesis leads to inflammosome activation, which is associated with asbestos induced pathology (Dostert <em>et al.</em>, 2008).</span></span></p>
<p><strong><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>Proteinosis, BALF protein content:</em></span></span></strong></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Compromised ACM barrier integrity <em>in vivo</em> can be measured by measuring total protein or total albumin content in the BALF derived from experimental animals exposed to lung toxicants or in human patients suffering from lung fibrosis. In addition to albumin, the total urea in BALF is also a good indicator of the ACM integrity loss (Schmekel et al., 1992).</span></span></p>
<p><strong><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>Cell type considerations:</em></span></span></strong></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ACM loss is a tissue level event. <em>In vitro</em>, assays with human cells are desired; however, the use of cells derived from experimental animals including alveolar macrophages, dendritic cells, epithelial cells, and neutrophils are routinely used. Primary cells are preferred over immortalised cell types that are in culture for a long period of time. <em>In vitro</em>, studies often assess the altered expression of pro-inflammatory mediators, increased ROS synthesis or oxidative stress and cytotoxicity events, an interplay between these three biological events occurring following exposure to stressors, is suggested to induce cell injury, which is reflective of tissue injury or loss of ACM (Halappanavar <em>et al.,</em> 2019) <em>in vivo</em>.</span></span></p>
<p><strong><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>Cytotoxicity assessment:</em></span></span></strong></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Cellular viability or cytotoxicity assays are the most commonly used endpoints to assess the leaky or compromised cell membrane. The most commonly employed method is the trypan blue exclusion assay – a dye exclusion assay where cells with intact membrane do not permit entry of the dye into cells and thus remain clear, whereas the dye diffuses into cells with damaged membrane turning them to blue colour. Other high throughput assays that use fluorescent DNA stains such as ethidium bromide or propidium iodide can also be used and cells that have incorporated the dye can be scored using flow cytometry. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Lactate dehydrogenase (LDH) release assay is a very sensitive cytotoxicity assay that measures the amount of LDH released in the media following membrane injury. The assay is based on measuring the reduction of nicotinamide adenine dinucleotide (NAD) and conversion of a tetrazolium dye that is measured at a wavelength of 490 nm.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The Calcein AM assay depends on the hydrolysis of calcein AM (a non-fluorescent hydrophobic compound that permeates live cells by simple diffusion) by non-specific intracellular esterases resulting in production of calcein, a hydrophilic and strongly fluorescent compound that is readily released into the cell culture media by the damaged cells.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Although the above mentioned assays work for almost all chemicals, insoluble substances such as nanomaterials can confound the assay by inhibiting the enzyme activity or interfering with the absorbance reading. Thus, care must be taken to include appropriate controls in the assays.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em>Transepithelial/transendothelial electrical resistance (TEER):</em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">TEER is an accepted quantitative technique that measures the integrity of tight junctions in cell culture models of endothelial and epithelial cell monolayers. They are based on measuring ohmic resistance or measuring impedance across a wide range of frequencies.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em>Other:</em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The other methods include targeted r</span></span><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">everse transcription polymerase chain reaction </span></span>(<span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RT-PCR) or e</span></span><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">nzyme-linked immunosorbent assays (</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ELISA) for tight junction proteins, cell adhesion molecules and inflammatory mediators such as Interferon gamma (IFN-</span></span><span style="font-size:11.0pt"><span style="font-family:"Arial",sans-serif">γ</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">), IL-10, and IL-13. Advanced <em>in vitro</em> co-culture models, like the EpiAlveolar model system, and other similar systems present an intact capillary membrane that can be used to assess loss in the membrane integrity (via TEER) after exposure to pro-fibrotic stressors like crystalline silica and Transforming growth factor beta (TGF-</span></span><span style="font-size:11.0pt"><span style="font-family:"Arial",sans-serif">β</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">) (Barasova <em>et al.,</em> 2020, Kasper <em>et al.,</em> 2011).</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">31. Tyurina YY, Kisin ER, Murray A, Tyurin VA, Kapralova VI, Sparvero LJ, Amoscato AA, Samhan-Arias AK, Swedin L, Lahesmaa R, Fadeel B, Shvedova AA, Kagan VE. Global phospholipidomics analysis reveals selective pulmonary peroxidation profiles upon inhalation of single-walled carbon nanotubes. ACS Nano. 2011 Sep 27;5(9):7342-53. doi: 10.1021/nn202201j. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">32. Yasuoka S, Nakayama T, Kawano T, Ogushi F, Doi H, Hayashi H, Tsubura E. Comparison of cell profiles of bronchial and bronchoalveolar lavage fluids between normal subjects and patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med. 1985 May;146(1):33-45. doi: 10.1620/tjem.146.33. </span></span></p>
2018-01-03T12:06:312023-05-17T15:35:29Inhibition of lung surfactant functionInhibition of LS function.Molecular<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Airborne substances that penetrate deep into the lungs and reach the alveoli will come into contact with the thin layer of lung surfactant prior to encountering the alveolar epithelial cells. In addition, blood components (such as albumin) that cross the alveolar-capillary membrane and reach the alveolar airspace can interact with the lung surfactant. The nature of this interaction between substances and lung surfactant depends on the origin (intrinsic versus extrinsic) of the substance, its molecular structure, size, and other physicochemical properties such as hydrophobicity, charge, etc. The interaction can be direct, with certain components of the lung surfactant film at the air-liquid interface i.e. by oxidation or cleaving of the phospholipids (Seeds, Grier et al. 2012, Stachowicz-Kusnierz, Cwiklik et al. 2018), or indirect, via competition with the adsorption of lung surfactant. In many cases, the interaction of substances with lung surfactant at the molecular level is responsible for lung surfactant function inhibition. </span></span></span></p>
<h3 style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><u><span style="font-family:"Calibri",sans-serif">Measurements of lung surfactant function inhibition</span></u></span></span></h3>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The inhibition of lung surfactant function can be measured <em>in vitro </em>by evaluating the surface activity in dynamic assays that mimic the continuous compression and expansion of the surfactant films at the air-liquid interface in the alveoli during breathing. Values of minimum surface tension, i.e. the lowest value of surface tension reached upon compression of the surfactant film, is a good indicator of the proper functioning of the lung surfactant. Maximum surface tension, i.e. the highest value of surface tension reached upon expansion of the lung surfactant film, reflects the effective re-adsorption of the lung surfactant at the interface. This parameter was shown to be less sensitive than the minimum surface tension to identify inhibitors of lung surfactant function </span><span style="font-family:"Calibri",sans-serif">(Valle, Wu et al. 2015, Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">. These tests can be performed in different setups. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Constrained drop surfactometer</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">In the constrained drop surfactometer (CDS) a droplet of lung surfactant is deposited on a sharp-edged pedestal, so that a surfactant film is formed at its air-water surface. The adsorbed lung surfactant film is cycled continuously, to mimic breathing </span><span style="font-family:"Calibri",sans-serif">(Zuo, Veldhuizen et al. 2008, Valle, Wu et al. 2015, Sørli, Da Silva et al. 2016, Yang, Wu et al. 2018)</span><span style="font-family:"Calibri",sans-serif">. A camera continuously takes pictures of the droplet before and during exposure to aerosols of the test substance at the air-liquid interface. Alternatively, the lung surfactant and the test substance can be mixed <em>prior to</em> deposition on the pedestal </span><span style="font-family:"Calibri",sans-serif">(Sørli, Låg et al. 2020)</span><span style="font-family:"Calibri",sans-serif">. Surface tension values are obtained by analysis of the drop shape in real-time </span><span style="font-family:"Calibri",sans-serif">(Yu, Yang et al. 2016)</span><span style="font-family:"Calibri",sans-serif">. The main advantages of this method include the accessibility of the air-liquid interface for exposure to airborne substances, flexibility in controlling cycling rates, and ease of determination of the surface tension in real-time while cycling the surfactant film. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Captive bubble surfactometer</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">In the captive bubble surfactometer (CBS), the lung surfactant film is formed at the air-liquid interface of an air bubble suspended in liquid. The function can be studied by injecting the test substance in the proximity of the surfactant layer at the interface between the air bubble and the surrounding liquid, or by mixing the substance and the surfactant <em>prior to</em> injecting the lung surfactant into the chamber. The captive bubble surfactometer allows study of the rapid initial adsorption of the lung surfactant at the air-liquid interface, post-expansion adsorption, surface activity during dynamic and quasi-static cycles, and stability of the surfactant film to mechanical perturbations </span><span style="font-family:"Calibri",sans-serif">(Autilio and Perez-Gil 2019)</span><span style="font-family:"Calibri",sans-serif">. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Pulsating bubble surfactometer</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">In the pulsating bubble surfactometer (PBS), an air bubble suspended on a capillary tube is formed in a chamber containing lung surfactant and is periodically compressed and expanded by a piston pulsator </span><span style="font-family:"Calibri",sans-serif">(Enhorning 2001, Autilio and Perez-Gil 2019)</span><span style="font-family:"Calibri",sans-serif">. The method has been used to study the effects of nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Schleh, Muhlfeld et al. 2009)</span><span style="font-family:"Calibri",sans-serif">, bacterial lipopolysaccharides </span><span style="font-family:"Calibri",sans-serif">(Kolomaznik, Liskayova et al. 2018)</span><span style="font-family:"Calibri",sans-serif">, glucocorticoids </span><span style="font-family:"Calibri",sans-serif">(Cimato, Facorro et al. 2018)</span><span style="font-family:"Calibri",sans-serif">, or meconium </span><span style="font-family:"Calibri",sans-serif">(Stichtenoth, Jung et al. 2006)</span><span style="font-family:"Calibri",sans-serif"> on lung surfactant. The pulsating bubble surfactometer was also used to investigate the surface activity of lung surfactant from patients with acute respiratory distress syndrome </span><span style="font-family:"Calibri",sans-serif">(Gregory, Longmore et al. 1991, Markart, Ruppert et al. 2007)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Capillary surfactometer</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">In the capillary surfactometer (CS), surfactant is deposited in a capillary tube of uneven diameter that simulate the cylindrical surfaces of the terminal conducting airways a constant airflow is led through the capillary. The percent of time with an open passage is used to assess the functionality of lung surfactant </span><span style="font-family:"Calibri",sans-serif">(Enhorning 2001, Larsen, Dallot et al. 2014, Sørli, Da Silva et al. 2016)</span><span style="font-family:"Calibri",sans-serif">. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Surfactant adsorption test</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The surfactant adsorption test is a fluorescence-based method that measures the extent and rate of adsorption of lung surfactant at the air-liquid interface. Lung surfactant is labelled with a fluorescent probe, and injected into the wells of a multi-well plate containing a light-absorbing agent (typically brilliant black). The plates are shaken and the fluorescence (of the lung surfactant sample reaching the surface of the wells) is measured. The fluorescence of the lung surfactant sample in the bulk (not adsorbed at the interface) is quenched by the light-adsorbing agent. This method is high-throughput compared to the biophysical assays described above and it allows to measure the effects of physiologically relevant factors, such as temperature, surfactant concentration, or presence of inhibitors in a high number of samples </span><span style="font-family:"Calibri",sans-serif">(Ravasio, Cruz et al. 2008)</span><span style="font-family:"Calibri",sans-serif">. However, this assay does not measure other biophysical properties like pressure-area isotherms, compressibility etc. </span></span></span></p>
<h3 style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><u><span style="font-family:"Calibri",sans-serif">Investigation of the interaction of a substance with lung surfactant</span></u></span></span></h3>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The interaction between a substance (exogenous airborne substances or biological components) and lung surfactant components can be investigated at the molecular level <em>in vitro </em>and estimated <em>in silico</em>. The methods rely on lung surfactant models, ranging from simple monolayers of dipalmitoylphosphatidylcholine (DPPC, the main surface-active component of lung surfactant), to the most complex native surfactant, obtained from broncho-alveolar lavage fluid or minced lung tissue. In most methods, a film of lung surfactant is formed at air-liquid interfaces and exposed to the substance of interest via aerosolisation or deposition. In some cases, the lung surfactant model is mixed directly with the test substance before spreading of the film.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Atomic force microscopy</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The topography of surfactant structures formed at respiratory-like air-liquid interfaces upon exposure to test substances can be studied by atomic force microscopy on fixed samples.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Langmuir-Blodgett films</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Langmuir-Blodgett films are interfacial films of surfactant transferred from the air-liquid interface onto solid supports. They are used to gain information about the distribution of lipids and proteins within the surfactant film and the effect of the interaction with test substances </span><span style="font-family:"Calibri",sans-serif">(Cruz and Perez-Gil 2007)</span><span style="font-family:"Calibri",sans-serif">. Surfactant films deposited at the air-liquid interface of a trough filled with liquid can be compressed by reducing the surface area of the trough. A sensor plate measures the variation in surface pressure over compression to yield surface pressure – area isotherms. It should be noted that in addition to the traditional Langmuir trough, the Langmuir-Blodgett technique has been adapted in the constrained drop surfactometer to study adsorbed surfactant films </span><span style="font-family:"Calibri",sans-serif">(Xu, Yang et al. 2020)</span><span style="font-family:"Calibri",sans-serif">. The comparison of such isotherms in the presence or absence of the test substance gives insights in the interaction of a substance with lung surfactant at the molecular level. Shifts in the surface pressure-area isotherms are identified most easily using simple models such as DPPC monolayers, but can also be seen using the more complex lung surfactant. Structural changes can be identified during compression of the film when combined with epifluorescence or atomic force microscopy. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Cryogenic transmission electron microscopy</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">In aqueous dispersions, lung surfactant forms vesicles. Cryogenic transmission electron microscopy allows visualizing morphological and structural changes at the single membrane vesicle level. After incubation with the test substance, the surfactant model is applied onto a carbon grid and vitrified in liquid ethane cooled by liquid nitrogen. Changes in the size, circularity or lamerallity of the vesicles indicate disruption of the three-dimensional surfactant structures. </span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif">Differential scanning calorimetry</span></em></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Differential scanning calorimetry allows the study of phase transitions occurring in lipid membranes (such as lung surfactant) over changes in temperature </span><span style="font-family:"Calibri",sans-serif">(Demetzos 2008)</span><span style="font-family:"Calibri",sans-serif">. It can be used to characterize the thermotropic phase behaviours of phospholipids in the surfactant models in the absence or presence of interacting substances. Associated enthalpy, transition temperature, and cooperativity can be estimated from the thermograms. It is a very sensitive method when working with simple models such as pure DPPC bilayers. The method is much less sensitive when using complex lung surfactant models. This is because several transitions overlap in membranes made of complex mixtures, each occurring at different temperature so it is difficult to identify one specific variation. </span></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The applicability domain is restricted to the groups of organisms where the structure and the functioning of the pulmonary system, including the lung surfactant, are conserved and relevant. Lung surfactant is a vital component of the lungs found in all major vertebrate groups, but particularly, to sustain the delicate structure of the mammalian lung. The lung surfactant system has a single point of origin and was a prerequisite for the evolution of air breathing </span><span style="font-family:"Calibri",sans-serif">(Sullivan, Daniels et al. 1998)</span><span style="font-family:"Calibri",sans-serif">. While the composition and function of lung surfactant are conserved in vertebrates, changes in composition among non-vertebrates are noted and likely reflect differences in the structure of the respiratory units </span><span style="font-family:"Calibri",sans-serif">(Veldhuizen, Nag et al. 1998)</span><span style="font-family:"Calibri",sans-serif">. Decreased lung function has been observed after exposure to airborne toxicants in humans of all sexes and ages, and in common experimental animal species, such as mice, rats, and rabbits.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Larsen, S. T., E. Da Silva, J. S. Hansen, A. C. O. Jensen, I. K. Koponen and J. B. Sørli (2020). "Acute Inhalation Toxicity After Inhalation of ZnO Nanoparticles: Lung Surfactant Function Inhibition In Vitro Correlates With Reduced Tidal Volume in Mice." <u>Int J Toxicol</u> <strong>39</strong>(4): 321-327.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Larsen, S. T., C. Dallot, S. W. Larsen, F. Rose, S. S. Poulsen, A. W. Nørgaard, J. S. Hansen, J. B. Sørli, G. D. Nielsen and C. Foged (2014). "Mechanism of action of lung damage caused by a nanofilm spray product." <u>Toxicol Sci</u> <strong>140</strong>(2): 436-444.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Lopez-Rodriguez, E., A. Cruz, R. P. Richter, H. W. Taeusch and J. Perez-Gil (2013). "Transient exposure of pulmonary surfactant to hyaluronan promotes structural and compositional transformations into a highly active state." <u>J Biol Chem</u> <strong>288</strong>(41): 29872-29881.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Lopez-Rodriguez, E., M. Echaide, A. Cruz, H. W. Taeusch and J. Perez-Gil (2011). "Meconium impairs pulmonary surfactant by a combined action of cholesterol and bile acids." <u>Biophys J</u> <strong>100</strong>(3): 646-655.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Lopez-Rodriguez, E., O. L. Ospina, M. Echaide, H. W. Taeusch and J. Perez-Gil (2012). "Exposure to polymers reverses inhibition of pulmonary surfactant by serum, meconium, or cholesterol in the captive bubble surfactometer." <u>Biophys J</u> <strong>103</strong>(7): 1451-1459.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Lugones, Y., O. Blanco, E. Lopez-Rodriguez, M. Echaide, A. Cruz and J. Perez-Gil (2018). "Inhibition and counterinhibition of Surfacen, a clinical lung surfactant of natural origin." <u>PLoS One</u> <strong>13</strong>(9): e0204050.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Markart, P., C. Ruppert, M. Wygrecka, T. Colaris, B. Dahal, D. Walmrath, H. Harbach, J. Wilhelm, W. Seeger, R. Schmidt and A. Guenther (2007). "Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids." <u>Thorax</u> <strong>62</strong>(7): 588-594.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Przybyla, R. J., J. Wright, R. Parthiban, S. Nazemidashtarjandi, S. Kaya and A. M. Farnoud (2017). "Electronic cigarette vapor alters the lateral structure but not tensiometric properties of calf lung surfactant." <u>Respir Res</u> <strong>18</strong>(1): 193.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Ravasio, A., A. Cruz, J. Perez-Gil and T. Haller (2008). "High-throughput evaluation of pulmonary surfactant adsorption and surface film formation." <u>J Lipid Res</u> <strong>49</strong>(11): 2479-2488.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Roldan, N., J. Perez-Gil, M. R. Morrow and B. Garcia-Alvarez (2017). "Divide & Conquer: Surfactant Protein SP-C and Cholesterol Modulate Phase Segregation in Lung Surfactant." <u>Biophys J</u> <strong>113</strong>(4): 847-859.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sachan, A. K., R. K. Harishchandra, C. Bantz, M. Maskos, R. Reichelt and H. J. Galla (2012). "High-resolution investigation of nanoparticle interaction with a model pulmonary surfactant monolayer." <u>ACS Nano</u> <strong>6</strong>(2): 1677-1687.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Schleh, C., C. Muhlfeld, K. Pulskamp, A. Schmiedl, M. Nassimi, H. D. Lauenstein, A. Braun, N. Krug, V. J. Erpenbeck and J. M. Hohlfeld (2009). "The effect of titanium dioxide nanoparticles on pulmonary surfactant function and ultrastructure." <u>Respir Res</u> <strong>10</strong>: 90.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Stenger, P. C., C. Alonso, J. A. Zasadzinski, A. J. Waring, C. L. Jung and K. E. Pinkerton (2009). "Environmental tobacco smoke effects on lung surfactant film organization." <u>Biochim Biophys Acta</u> <strong>1788</strong>(2): 358-370.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Stichtenoth, G., P. Jung, G. Walter, J. Johansson, B. Robertson, T. Curstedt and E. Herting (2006). "Polymyxin B/pulmonary surfactant mixtures have increased resistance to inactivation by meconium and reduce growth of gram-negative bacteria in vitro." <u>Pediatr Res</u> <strong>59</strong>(3): 407-411.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sullivan, L. C., C. B. Daniels, I. D. Phillips, S. Orgeig and J. A. Whitsett (1998). "Conservation of surfactant protein A: evidence for a single origin for vertebrate pulmonary surfactant." <u>J Mol Evol</u> <strong>46</strong>(2): 131-138.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sørli, J. B., K. Balogh Sivars, E. Da Silva, K. S. Hougaard, I. K. Koponen, Y. Y. Zuo, I. E. K. Weydahl, P. M. Åberg and R. Fransson (2018). "Bile salt enhancers for inhalation: Correlation between in vitro and in vivo lung effects." <u>Int J Pharm</u> <strong>550</strong>(1-2): 114-122.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sørli, J. B., E. Da Silva, P. Backman, M. Levin, B. L. Thomsen, I. K. Koponen and S. T. Larsen (2016). "A Proposed In Vitro Method to Assess Effects of Inhaled Particles on Lung Surfactant Function." <u>Am J Respir Cell Mol Biol</u> <strong>54</strong>(3): 306-311.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sørli, J. B., Y. Huang, E. Da Silva, J. S. Hansen, Y. Y. Zuo, M. Frederiksen, A. W. Nørgaard, N. E. Ebbehøj, S. T. Larsen and K. S. Hougaard (2018). "Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition." <u>ALTEX</u> <strong>35</strong>(1): 26-36.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Sørli, J. B., M. Låg, L. Ekeren, J. Perez-Gil, L. S. Haug, E. Da Silva, M. N. Matrod, K. B. Gutzkow and B. Lindeman (2020). "Per- and polyfluoroalkyl substances (PFASs) modify lung surfactant function and pro-inflammatory responses in human bronchial epithelial cells." <u>Toxicol In Vitro</u> <strong>62</strong>: 104656.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Taeusch, H. W., J. Bernardino de la Serna, J. Perez-Gil, C. Alonso and J. A. Zasadzinski (2005). "Inactivation of pulmonary surfactant due to serum-inhibited adsorption and reversal by hydrophilic polymers: experimental." <u>Biophys J</u> <strong>89</strong>(3): 1769-1779.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Tatur, S. and A. Badia (2012). "Influence of hydrophobic alkylated gold nanoparticles on the phase behavior of monolayers of DPPC and clinical lung surfactant." <u>Langmuir</u> <strong>28</strong>(1): 628-639.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Valle, R. P., T. Wu and Y. Y. Zuo (2015). "Biophysical influence of airborne carbon nanomaterials on natural pulmonary surfactant." <u>ACS Nano</u> <strong>9</strong>(5): 5413-5421.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Veldhuizen, R., K. Nag, S. Orgeig and F. Possmayer (1998). "The role of lipids in pulmonary surfactant." <u>Biochim Biophys Acta</u> <strong>1408</strong>(2-3): 90-108.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Wang, F., J. Liu and H. Zeng (2020). "Interactions of particulate matter and pulmonary surfactant: Implications for human health." <u>Adv Colloid Interface Sci</u> <strong>284</strong>: 102244.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Wang, Y. E., H. Zhang, Q. Fan, C. R. Neal and Y. Y. Zuo (2012). "Biophysical interaction between corticosteroids and natural surfactant preparation: implications for pulmonary drug delivery using surfactant a a carrier." <u>Soft Matter</u> <strong>8</strong>(2): 504-511.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Xu, L., Y. Yang and Y. Y. Zuo (2020). "Atomic Force Microscopy Imaging of Adsorbed Pulmonary Surfactant Films." <u>Biophys J</u> <strong>119</strong>(4): 756-766.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Xu, Y., Z. Luo, S. Li, W. Li, X. Zhang, Y. Y. Zuo, F. Huang and T. Yue (2017). "Perturbation of the pulmonary surfactant monolayer by single-walled carbon nanotubes: a molecular dynamics study." <u>Nanoscale</u> <strong>9</strong>(29): 10193-10204.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Yang, Y., Y. K. Wu, Q. Z. Ren, L. G. Zhang, S. J. Liu and Y. Y. Zuo (2018). "Biophysical Assessment of Pulmonary Surfactant Predicts the Lung Toxicity of Nanomaterials." <u>Small Methods</u> <strong>2</strong>(4).</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Yang, Y., L. Xu, S. Dekkers, L. G. Zhang, F. R. Cassee and Y. Y. Zuo (2018). "Aggregation State of Metal-Based Nanomaterials at the Pulmonary Surfactant Film Determines Biophysical Inhibition." <u>Environ Sci Technol</u> <strong>52</strong>(15): 8920-8929.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Yu, K., J. Yang and Y. Y. Zuo (2016). "Automated Droplet Manipulation Using Closed-Loop Axisymmetric Drop Shape Analysis." <u>Langmuir</u> <strong>32</strong>(19): 4820-4826.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Yuan, Y., X. Liu, T. Liu, W. Liu, Y. Zhu, H. Zhang and C. Zhao (2020). "Molecular dynamics exploring of atmosphere components interacting with lung surfactant phospholipid bilayers." <u>Sci Total Environ</u> <strong>743</strong>: 140547.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Zhang, H., Y. E. Wang, C. R. Neal and Y. Y. Zuo (2012). "Differential effects of cholesterol and budesonide on biophysical properties of clinical surfactant." <u>Pediatr Res</u> <strong>71</strong>(4 Pt 1): 316-323.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Zhao, Q., Y. Li, X. Chai, L. Xu, L. Zhang, P. Ning, J. Huang and S. Tian (2019). "Interaction of inhalable volatile organic compounds and pulmonary surfactant: Potential hazards of VOCs exposure to lung." <u>J Hazard Mater</u> <strong>369</strong>: 512-520.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Zuo, Y. Y., R. A. Veldhuizen, A. W. Neumann, N. O. Petersen and F. Possmayer (2008). "Current perspectives in pulmonary surfactant--inhibition, enhancement and evaluation." <u>Biochim Biophys Acta</u> <strong>1778</strong>(10): 1947-1977.</span></span></p>
<p style="text-align:justify"> </p>
2019-07-03T13:16:042021-10-27T11:13:08Alveolar collapseAlveolar collapseCellular<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">At the end of expiration, the alveoli are at their minimum volume, and the surface tension is at its lowest. If the surface tension is not sufficiently low at this point, the forces pulling the walls of the alveoli together during expiration cannot be overcome, and the alveoli might collapse </span><span style="font-family:"Calibri",sans-serif">(Notter and Wang 1997)</span><span style="font-family:"Calibri",sans-serif">. Collapsed alveoli may however be re-opened by the force of air drawn into the lungs during inhalation. As breathing is continuous, the same alveoli can collapse and re-open repeatedly. The consequence of alveolar collapse can be observed as atelectasis upon histological examination, or can be indirectly inferred by reduced tidal volume or perfusion/ventilation mismatch (further details in the “Measurements of alveolar collapse” section).</span></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">There are approximately 480 million alveoli in the lungs </span><span style="font-family:"Calibri",sans-serif">(Ochs, Nyengaard et al. 2004)</span><span style="font-family:"Calibri",sans-serif">. Alveolar collapse and re-opening can only happen in intact lungs in a living organism and thus cannot be measured <em>in vitro</em>. Further, because of their small diameter of approximately 200 µm in diameter </span><span style="font-family:"Calibri",sans-serif">(Ochs, Nyengaard et al. 2004)</span><span style="font-family:"Calibri",sans-serif">, it is virtually impossible to measure the collapse and re-opening at the level of individual alveoli with any certainty. However, areas of atelectasis can be observed in experimental animals after staining of lung tissue from exposed animals </span><span style="font-family:"Calibri",sans-serif">(Jefferies, Kawano et al. 1988, Yamashita and Tanaka 1995, Nørgaard, Larsen et al. 2010)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The applicability domain is restricted to the groups of organisms where the structure and the functioning of the pulmonary system, including the alveoli, are conserved and relevant.</span></span></span></p>
HighMixedHighAll life stagesHighHighModerate<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Jefferies, A. L., T. Kawano, S. Mori and R. Burger (1988). "Effect of increased surface tension and assisted ventilation on 99mTc-DTPA clearance." <u>J Appl Physiol (1985)</u> <strong>64</strong>(2): 562-568.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Notter, R. H. and Z. D. Wang (1997). "Pulmonary surfactant: Physical chemistry, physiology, and replacement." <u>Reviews in Chemical Engineering</u> <strong>13</strong>(4): 1-118.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Nørgaard, A. W., S. T. Larsen, M. Hammer, S. S. Poulsen, K. A. Jensen, G. D. Nielsen and P. Wolkoff (2010). "Lung damage in mice after inhalation of nanofilm spray products: the role of perfluorination and free hydroxyl groups." <u>Toxicol Sci</u> <strong>116</strong>(1): 216-224.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Ochs, M., J. R. Nyengaard, A. Jung, L. Knudsen, M. Voigt, T. Wahlers, J. Richter and H. J. Gundersen (2004). "The number of alveoli in the human lung." <u>Am J Respir Crit Care Med</u> <strong>169</strong>(1): 120-124.</span></span></p>
<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif">Yamashita, M. and J. Tanaka (1995). "Pulmonary Collapse and Pneumonia Due to Inhalation of a Waterproofing Aerosol in Female Cd-1 Mice." <u>Journal of Toxicology-Clinical Toxicology</u> <strong>33</strong>(6): 631-637.</span></span></p>
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2019-07-03T13:16:412021-10-27T11:33:26Decrease, Lung functionDecreased lung functionIndividual<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Segoe UI",sans-serif">Lung function is a clinical term referring to the physiological functioning of the lungs, most often in association with the tests used to assess it. Lung function loss can be caused by acute or chronic exposure to airborne toxicants or by an intrinsic disease of the respiratory system. </span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Although signs of cellular injury are typically exhibited first in the nose and larynx, alveolar-capillary barrier breakdown may ultimately arise and result in local edema (Miller and Chang, 2003). Clinically, bronchoconstriction and hypoxia are seen in the acute phase, with affected subjects exhibiting shortness of breath (dyspnea) and low blood oxygen saturation, and with reduced lung function indices of airflow, lung volume and gas exchange (Hert and Albert, 1994; and How it is Measured or Detected;). When alveolar damage is extensive, the reduced lung function can develop into acute respiratory distress syndrome (ARDS). This severe compromise of lung function is reflected by decreased gas exchange indices (PaO<sub>2</sub>/FIO<sub>2</sub> ≤200 mmHg, due to hypoxemia and impaired excretion of carbon dioxide), increased pulmonary dead space and decreased respiratory compliance (Matthay et al., 2019). Acute inhalation exposures to chemical irritants such as ammonia, hydrogen chloride, nitrogen oxides and ozone typically cause local edema that manifests as dyspnea and hypoxia. In cases where a breakdown of the alveolar capillary function ensues, ARDS develops. ARDS has a particularly high risk of mortality, estimated to be 30-40% (Gorguner and Akgun, 2010; Matthay et al., 2018; Reilly et al., 2019).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Lung function decrease due to reduction in lung volume is seen in pulmonary fibrosis, which can be linked to chronic exposures to e.g. silica, asbestos, metals, agricultural and animal dusts (Meltzer and Noble, 2008; Cheresh et al., 2013; Cosgrove, 2015; Trethewey and Walters, 2018). Additionally. decreased lung function occurs in pleural disease, chest wall and neuromuscular disorders, because of obesity and following pneumectomy (Moore, 2012). Decreased lung function can also be a result of narrowing of the airways by inflammation and mucus plugging resulting in airflow limitation. Decreased lung function is a feature of obstructive pulmonary diseases (e.g. asthma, COPD) and linked to a multitude of causes, including chronic exposure to cigarette smoke, dust, metals, organic solvents, asbestos, pathogens or genetic factors. </span></span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Pulmonary function tests are a group of tests that evaluate several parameters indicative of lung size, air flow and gas exchange. Decreased lung function can manifest in different ways, and individual circumstances, including potential exposure scenarios, determine which test is used. The section outlines the tests used to evaluate lung function in humans (https://www.nhlbi.nih.gov/health-topics/pulmonary-function-tests, accessed 22 March 2021) and in experimental animals.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><strong><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Lung function tests used to evaluate human lung function</span></span></strong></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">The most common (“gold standard”) lung function test in human subjects is spirometry. Spirometry results are primarily used for diagnostic purposes, e.g. to discriminate between obstructive and restrictive lung diseases, and for determining the degree of lung function impairment. Specific criteria for spirometry tests have been outlined in the American Thoracic Society (ATS) and the European Respiratory Society (ERS) Task Force guidelines (Graham et al., 2019). These guidelines consist of detailed recommendations for the preparation and conduct of the test, instruction of the person tested, as well as indications and contraindications, and are complemented by additional guidance documents on how to interpret and report the test results (Pellegrino et al., 2005; Culver et al., 2017).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Spirometry measures several different parameters during forceful exhalation, including:</span></span></span></span></span></p>
<ul>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Forced expiratory volume in 1 s (FEV1), the maximum volume of air that can forcibly be exhaled during the first second following maximal inhalation</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Forced vital capacity (FVC), the maximum volume of air that can forcibly be exhaled following maximal inhalation </span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Vital capacity (VC), the maximum volume of air that can be exhaled when exhaling as fast as possible</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">FEV1/FVC ratio</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Peak expiratory flow (PEF), the maximal flow that can be exhaled when exhaling at a steady rate</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Forced expiratory flow, also known as mid-expiratory flow; the rates at 25%, 50% and 75% FVC are given</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Inspiratory vital capacity (IVC), the maximum volume of air that can be inhaled after a full expiration</span></span></span></span></span></li>
</ul>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">A reduced FEV1, with normal or reduced VC, normal or reduced FVC, and a reduced FEV1/FVC ratio are indices of airflow limitation, i.e., airway obstruction as seen in COPD (Moore, 2012). In contrast, airway restriction is demonstrated by a reduction in FVC, normal or increased FEV1/FVC ratio, a normal spirometry trace and potentially a high PEF (Moore, 2012).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Lung capacity or lung volumes can be measured using one of three basic techniques: 1) plethysmography, 2) nitrogen washout, or 3) helium dilution. Plethysmography consists of a series of sequential measurements in a body plethysmograph, starting with the measurement of functional residual capacity (FRC),</span></span> <span style="font-family:"Segoe UI",sans-serif"><span style="color:black">the volume of gas present in the lung at end-expiration during tidal breathing. Once the FRC is known, expiratory reserve volume (ERV; the volume of gas that can be maximally exhaled from the end-expiratory level during tidal breathing, i.e., the FRC), vital capacity (VC; the volume change at the mouth between the positions of full inspiration and complete expiration), and inspiratory capacity (IC; the maximum volume of air that can be inhaled from FRC) are determined, and total lung capacity (TLC;</span></span> <span style="font-family:"Segoe UI",sans-serif"><span style="color:black">the volume of gas in the lungs after maximal inspiration, or the sum of all volume compartments) and residual volume (RV; the volume of gas remaining in the lung after maximal exhalation) are calculated (Weinstock and McCannon, 2017).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">The other two techniques used to measure lung volumes—helium dilution and nitrogen washout—are based on the principle of conservation of mass: [initial gas concentration] x [initial volume of the system] = [final gas concentration] x [final volume of the system]. The nitrogen washout method is based on the fact that nitrogen is present in the air, at a relatively constant amount. The subject is given 100% oxygen to breathe, and the expired gas, which contains nitrogen in the lung at the beginning of the test, is collected. When no more nitrogen is noted in the expirate, the volume of air expired and the entire amount of nitrogen in that volume are measured, and the initial volume of the system (FRC) can be calculated. In the helium dilution method, a known volume and concentration of helium is inhaled by the subject. Helium, an inert gas that is not absorbed significantly from the lungs, is diluted in proportion to the lung volume to which it is added. The final concentration of helium is then measured and FRC calculated (Weinstock and McCannon, 2017).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Measurements of lung volumes in humans are technically more challenging than spirometry. However, they complement spirometry (which cannot determine lung volumes) and may be a preferred means of lung function assessment when subject compliance cannot be reasonably expected (e.g. in pediatric subjects) or where forced expiratory maneuvers are not possible (e.g. in patients with advanced pulmonary fibrosis). There are recommended standards for lung volume measurements and their interpretation in clinical practice, issued by the ATS/ERS Task Force (Wanger et al., 2005; Criée et al., 2011). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Finally, indices of gas exchange across the alveolar-capillary barrier are tested by diffusion capacity of carbon monoxide (DLCO) studies (also referred to as transfer capacity of carbon monoxide, TLCO). The principle of the test is the increased affinity of hemoglobin to preferentially bind carbon monoxide over oxygen (Weinstock and McCannon, 2017). Complementary to spirometry and lung volume measurements, DLCO provides information about the lung surface area available for gas diffusion. Therefore, it is sensitive to any structural changes affecting the alveoli, such as those accompanying emphysema, pulmonary fibrosis, pulmonary edema, and ARDS. Recommendations for the standardization of the test and its evaluation have been outlined by the ATS/ERS Task Force (Graham et al., 2017). An isolated reduction in DLCO with normal spirometry and in absence of anemia suggests an injury to the alveolar-capillary barrier, as for example seen in the presence of pulmonary emboli or in patients with pulmonary hypertension (Weinstock and McCannon, 2017; Lettieri et al., 2006; Seeger et al., 2013). Reduced DLCO together with airflow obstruction (i.e., reduced FEV1) indicates lung parenchymal damage and is commonly observed in smokers and in COPD patients (Matheson et al., 2007; Harvey et al., 2016), whereas reduced DLCO with airflow restriction is seen in patients with interstitial lung diseases (Dias et al., 2014; Kandhare et al., 2016).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><strong><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Lung function tests used to evaluate experimental animal lung function</span></span></strong></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Because spirometry requires active participation and compliance of the subject, it is not commonly used in animal studies. However, specialized equipment such as the flexiVent system (SCIREQ<sup>®</sup>) are available for measuring FEV, FVC and PEF in anesthetized and tracheotomized small laboratory animals. Other techniques such as plethysmography or forced oscillation are increasingly preferred for lung function assessment in small laboratory animals (McGovern et al., 2013; Bates, 2017). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">In small laboratory animals, plethysmography can be used to determine respiratory physiology parameters (minute volume, respiratory rate, time of pause and time of break), lung volume and airway resistance of conscious animals. Both whole body and head-out plethysmography can be applied, although there is a preference for the latter in the context of inhalation toxicity studies, because of its higher accuracy and reliability (OECD, 2018a; Hoymann, 2012).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Gas diffusion tests are not frequently performed in animals, because reproducible samplings of alveolar gas are difficult and technically challenging (Reinhard et al., 2002; Fallica et al., 2011). Modifications to the procedure employed in humans have, however, open possibilities to obtain a human-equivalent DLCO measure or the diffusion factor for carbon monoxide (DFCO)—a variable closely related to DLCO, which can inform on potential structural changes in the lungs that have an effect on gas exchange indices (Takezawa et al., 1980; Dalbey et al., 1987; Fallica et al., 2011; Limjunyawong et al., 2015).</span></span></span></span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Pulmonary function tests reflect the physiological working of the lungs. Therefore, the AO is applicable to a variety of species, including (but not limited to) rodents, rabbits, pigs, cats, dogs, horses and humans, independent of life stage and gender.</span></span></span></span></span></p>
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</div>
2016-11-29T18:41:312021-09-08T04:54:28275a7727-97ae-4c7d-bed7-2e3bd5bb2489dfc58eef-a03e-4766-aa23-45f39e7fc68bHighMixedHighAll life stagesModerateHighModerate2019-07-03T13:21:452019-07-03T13:21:45275a7727-97ae-4c7d-bed7-2e3bd5bb2489127ae12b-c682-4c07-ab65-cc3e92b47bfe2021-04-27T08:21:032021-04-27T08:21:03dfc58eef-a03e-4766-aa23-45f39e7fc68b2d86c70a-ba16-43d4-94f3-97cadeda8bf12019-07-03T13:24:182019-07-03T13:24:18dfc58eef-a03e-4766-aa23-45f39e7fc68b127ae12b-c682-4c07-ab65-cc3e92b47bfe2021-04-27T08:21:192021-04-27T08:21:19dfc58eef-a03e-4766-aa23-45f39e7fc68b0482bc64-afcd-45d3-850e-83ffd38bcda5<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:9.0pt">Alveolar collapse (KE 1673) (KE upstream) results from high surface tension in the alveoli, particularly at the end of expiration (when the surface area of the alveoli are at their smallest). Alveolar collapse is difficult to measure on the individual level as collapsed alveoli may open with in breath, but then collapse again. The opening and closing of the alveoli puts stress on the alveolar-capillary membrane that is enhanced in case of additional high surface tension, resulting in loss of integrity between the blood and the air in the lungs (KE 1498) KEdownstream).</span></span></span></p>
HighMixedModerateAll life stagesModerateHighModerate2021-02-16T11:59:262022-02-01T05:42:290482bc64-afcd-45d3-850e-83ffd38bcda5127ae12b-c682-4c07-ab65-cc3e92b47bfe2021-04-27T08:21:342021-04-27T08:21:342d86c70a-ba16-43d4-94f3-97cadeda8bf1127ae12b-c682-4c07-ab65-cc3e92b47bfe2021-04-27T08:19:292021-04-27T08:19:290482bc64-afcd-45d3-850e-83ffd38bcda5275a7727-97ae-4c7d-bed7-2e3bd5bb24892021-04-27T08:19:582021-04-27T08:19:580482bc64-afcd-45d3-850e-83ffd38bcda52d86c70a-ba16-43d4-94f3-97cadeda8bf12021-04-27T08:20:452021-04-27T08:20:45Lung surfactant function inhibition leading to decreased lung functionLung surfactant function inhibition leading to decreased lung functionOpen for comment. Do not citeUnder DevelopmentIncluded in OECD Work Plan1.87<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Inhalation of substances, chemicals, particles and mixtures is the main route of occupational exposure. This adverse outcome pathway (AOP) describes the connections between the inhibition of lung surfactant function, and how this is connected to decreased lung function. Lung surfactant is a thin layer of lipids and proteins that lines the respiratory parts of the lungs. Decreased lung function in humans is characterized by symptoms such as coughing, difficult breathing, tightness in the chest, fever and vomiting (AO) [1, 2]. In experimental animals acute inhalation toxicity is defined as the total of adverse effects caused by a substance following a single uninterrupted exposure by inhalation over a short period of time (24 hours or less) to a substance capable of being inhaled [3]. This AOP describes one of the pathways that can lead to decreased lung function seen as respiratory clinical signs of toxicity in humans and experimental animals. </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">The main function of lung surfactant is to lower the surface tension at the air-liquid interface during the breathing cycle. Inhaling substances that reach the alveoli can potentially interact with and inhibit the lung surfactant function (MIE). Inhibition leads to an increase in minimum surface tension and alveolar collapse (KE1), the individual alveoli can stay closed or be open again by the force of the inhaled air. If the alveolus stays closed, this reduces the tidal volume (KE3), reducing the area for gas exchange in the lungs and reduces blood oxygenation (hypoxemia). If the alveolus reopens, this can lead to loss of capillary membrane integrity due to shear stress on the epithelium (KE2) and bleeding into the lungs. Blood components (such as albumin and fibrin) reaching the air-liquid interface will further disrupt lung surfactant function by interacting with the lung surfactant (feedback loop between KE2 and MIE) [4-7] leading to the exacerbation of the process. The combination of alveolar collapse, loss of capillary membrane integrity and reduced tidal volume leads to decreased lung function. The MIE (lung surfactant function inhibition) can be examined <em>in vitro</em> by measuring the effect of a substance or mixture of substances on the lung surfactant function. The effects of blood entering the lung and interacting with lung surfactant can likewise be studied in the <em>in vitro </em>assay. Reduced tidal volume can be measured <em>in vivo</em>, using experimental animals in whole body plethysmographs that are exposed to the substance in question, while monitoring respiration parameters. The effect of reduced tidal volume, hypoxemia, can be measured by analysing the oxygenation of the blood both from experimental animals, and patients that have inhaled substances leading to immediate adverse lung effects. The loss of capillary membrane integrity can be examined in experimental animals, by analysing liquid flushed from the lungs (broncho-alveolar lavage), and in lavage from patients undergoing examination during acute lung injury [8]. </span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Decreased lung function is observed frequently in humans [2]. Similar symptoms are seen in experimental animals [1]. Lung surfactant function impairment <em>in vitro</em> has been strongly associated with induction of acute lung toxicity both in humans and in experimental animals [1]. </span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">In addition to lung surfactant function impairment, there are potentially several other pathways leading to decreased lung function, e.g. inflammatory cells activation, activation of the immune system, damage to the epithelial cells of the lungs, interaction with the nervous system in the lungs; however other AOPs may describe this process, and can be linked to this proposed AOP. Additionally decreased lung function may have long term effects on the lungs, such as development of fibrosis (AOP 173) or asthma and COPD (AOP 196 and AOP 148).</span></span></span></span></p>
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<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Sørli, J.B., et al., <em>Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition.</em> ALTEX, 2017. <strong>35</strong>(1): p. 26-36.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Alexeeff, G.V., et al., <em>Characterization of the LOAEL-to-NOAEL uncertainty factor for mild adverse effects from acute inhalation exposures.</em> Regul Toxicol Pharmacol, 2002. <strong>36</strong>(1): p. 96-105. </span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">OECD (2018). "Guidance document on inhalation toxicity studies series on testing and assessment No. 39 (Second Edition)."</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Banerjee, R.R., <em>Interactions between hematological derivatives and dipalmitoyl phosphatidyl choline: implications for adult respiratory distress syndrome.</em> Colloids Surf. B Biointerfaces, 2004. <strong>34</strong>(2): p. 95-104.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Gunasekara, L., et al., <em>A comparative study of mechanisms of surfactant inhibition.</em> Biochim. Biophys. Acta, 2008. <strong>1778</strong>(2): p. 433-444.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Gunther, A., et al., <em>Surfactant alteration and replacement in acute respiratory distress syndrome.</em> Respir. Res, 2001. <strong>2</strong>(6): p. 353-364.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Zuo, Y.Y., et al., <em>Chitosan enhances the in vitro surface activity of dilute lung surfactant preparations and resists albumin-induced inactivation.</em> Pediatr. Res, 2006. <strong>60</strong>(2): p. 125-130.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Nakos, G., et al., <em>Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components.</em> Intensive Care Med, 1998. <strong>24</strong>(4): p. 296-303.</span></span></span></span></li>
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<h3 style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><u>Inhibition of lung surfactant function</u></span></span></h3>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The constrained drop surfactometer has been applied to the exposure to a broad range of substances, including nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Fan, Wang et al. 2011, Valle, Wu et al. 2015, Yang, Xu et al. 2018, Larsen, Da Silva et al. 2020, Wang, Liu et al. 2020)</span><span style="font-family:"Calibri",sans-serif">, individual chemicals </span><span style="font-family:"Calibri",sans-serif">(Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, mixtures of chemicals </span><span style="font-family:"Calibri",sans-serif">(Sørli, Da Silva et al. 2016, Sørli, Huang et al. 2018, Da Silva, Hickey et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, excipients for drug formulation </span><span style="font-family:"Calibri",sans-serif">(Sørli, Balogh Sivars et al. 2018)</span><span style="font-family:"Calibri",sans-serif">, per- and poly-fluoroalkyl substances </span><span style="font-family:"Calibri",sans-serif">(Sørli, Låg et al. 2020)</span><span style="font-family:"Calibri",sans-serif">, or plasma </span><span style="font-family:"Calibri",sans-serif">(Autilio, Echaide et al. 2021)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The captive bubble surfactometer has been applied to investigation of industrial chemicals </span><span style="font-family:"Calibri",sans-serif">(Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Bakshi, Zhao et al. 2008)</span><span style="font-family:"Calibri",sans-serif">, cholesterol </span><span style="font-family:"Calibri",sans-serif">(Gunasekara, Schurch et al. 2005, Gomez-Gil, Schurch et al. 2009, Lopez-Rodriguez, Ospina et al. 2012)</span><span style="font-family:"Calibri",sans-serif">, meconium </span><span style="font-family:"Calibri",sans-serif">(Lopez-Rodriguez, Echaide et al. 2011, Lopez-Rodriguez, Ospina et al. 2012)</span><span style="font-family:"Calibri",sans-serif">, plasma </span><span style="font-family:"Calibri",sans-serif">(Autilio, Echaide et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, serum </span><span style="font-family:"Calibri",sans-serif">(Lopez-Rodriguez, Ospina et al. 2012, Lopez-Rodriguez, Cruz et al. 2013, Lugones, Blanco et al. 2018)</span><span style="font-family:"Calibri",sans-serif">, corticosteroids </span><span style="font-family:"Calibri",sans-serif">(Hidalgo, Salomone et al. 2017)</span><span style="font-family:"Calibri",sans-serif">, or cyclodextrines on lung surfactant </span><span style="font-family:"Calibri",sans-serif">(Al-Saiedy, Gunasekara et al. 2018)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">The surfactant adsorpion test h</span><span style="font-family:"Calibri",sans-serif">as been used to study how albumin at the air-liquid interface hinders adsorption of lamellar body like particles </span><span style="font-family:"Calibri",sans-serif">(Hobi, Siber et al. 2014)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<h3 style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><u>Interaction with lung surfactant</u></span></span></h3>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Atomic force microscopy </span><span style="font-family:"Calibri",sans-serif">has been extensively used with nanoparticles (including gold nanoparticles, graphene oxide, carbon nanotubes) in order to characterize their presence within surfactant films, to identify interactions with surface-associated structures, and to study the retention at the interface upon film compression </span><span style="font-family:"Calibri",sans-serif">(Sachan, Harishchandra et al. 2012, Tatur and Badia 2012, Hu, Jiao et al. 2013, Valle, Wu et al. 2015, Yang, Xu et al. 2018)</span><span style="font-family:"Calibri",sans-serif">. Atomic force microscopy has also been used to compare the molecular organization and lateral structure of surfactant models in the presence and absence of corticosteroids </span><span style="font-family:"Calibri",sans-serif">(Wang, Zhang et al. 2012)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Langmuir-Blodgett films </span><span style="font-family:"Calibri",sans-serif">have been applied successfully to the study of changes induced by resin acids </span><span style="font-family:"Calibri",sans-serif">(Jagalski, Barker et al. 2016)</span><span style="font-family:"Calibri",sans-serif">, nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Wang, Liu et al. 2020)</span><span style="font-family:"Calibri",sans-serif">, soot particles </span><span style="font-family:"Calibri",sans-serif">(Fang, Zhao et al. 2020)</span><span style="font-family:"Calibri",sans-serif">, volatile organic substances </span><span style="font-family:"Calibri",sans-serif">(Zhao, Li et al. 2019)</span><span style="font-family:"Calibri",sans-serif">, industrial chemicals </span><span style="font-family:"Calibri",sans-serif">(Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, tobacco smoke constituents </span><span style="font-family:"Calibri",sans-serif">(Stenger, Alonso et al. 2009)</span><span style="font-family:"Calibri",sans-serif">, e-cigarette components </span><span style="font-family:"Calibri",sans-serif">(Przybyla, Wright et al. 2017)</span><span style="font-family:"Calibri",sans-serif">, spray products </span><span style="font-family:"Calibri",sans-serif">(Larsen, Dallot et al. 2014)</span><span style="font-family:"Calibri",sans-serif">, corticosteroids </span><span style="font-family:"Calibri",sans-serif">(Wang, Zhang et al. 2012)</span><span style="font-family:"Calibri",sans-serif">, and biological components like cholesterol </span><span style="font-family:"Calibri",sans-serif">(Taeusch, Bernardino de la Serna et al. 2005, Zhang, Wang et al. 2012)</span><span style="font-family:"Calibri",sans-serif">, or meconium </span><span style="font-family:"Calibri",sans-serif">(Lopez-Rodriguez, Echaide et al. 2011)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Cryogenic transmission electron microscopy was applied to study the effects of industrial chemicals </span><span style="font-family:"Calibri",sans-serif">(Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, resin acids </span><span style="font-family:"Calibri",sans-serif">(Jagalski, Barker et al. 2016)</span><span style="font-family:"Calibri",sans-serif">, meconium </span><span style="font-family:"Calibri",sans-serif">(Gross, Zmora et al. 2006, Autilio, Echaide et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, and nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Fan, Wang et al. 2011)</span> <span style="font-family:"Calibri",sans-serif">on native surfactant.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">Differential scanning calorimetry has been used to investigate the effects of meconium </span><span style="font-family:"Calibri",sans-serif">(Lopez-Rodriguez, Echaide et al. 2011)</span><span style="font-family:"Calibri",sans-serif">, cholesterol </span><span style="font-family:"Calibri",sans-serif">(Roldan, Perez-Gil et al. 2017)</span><span style="font-family:"Calibri",sans-serif">, industrial chemicals </span><span style="font-family:"Calibri",sans-serif">(Da Silva, Autilio et al. 2021)</span><span style="font-family:"Calibri",sans-serif">, or resin acids </span><span style="font-family:"Calibri",sans-serif">(Jagalski, Barker et al. 2016)</span><span style="font-family:"Calibri",sans-serif"> on various membrane models.</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:13pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif">A range of other methods allows to investigate the interaction of a substance with lung surfactant. Binding of lung surfactant components on nanoparticles was shown by proteomics and lipidomics analysis of the corona after incubation <em>in vitro</em> </span><span style="font-family:"Calibri",sans-serif">(Gasser, Rothen-Rutishauser et al. 2010)</span><span style="font-family:"Calibri",sans-serif"> or after exposure of rodents and broncho-alveolar lavage fluid isolation </span><span style="font-family:"Calibri",sans-serif">(Kapralov, Feng et al. 2012)</span><span style="font-family:"Calibri",sans-serif">. Molecular dynamics simulations <em>in silico </em>have been successfully used to investigate the interaction of atmosphere components with lung surfactant </span><span style="font-family:"Calibri",sans-serif">(Yuan, Liu et al. 2020)</span><span style="font-family:"Calibri",sans-serif">, particularly single-wall carbon nanotubes </span><span style="font-family:"Calibri",sans-serif">(Xu, Luo et al. 2017)</span><span style="font-family:"Calibri",sans-serif">, and hydrophilic (hydroxyapatite, silver) and hydrophobic (polystyrene) nanoparticles </span><span style="font-family:"Calibri",sans-serif">(Hu, Jiao et al. 2013, Hu, Bai et al. 2017)</span><span style="font-family:"Calibri",sans-serif">.</span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Established regulatory guideline studies for inhalation toxicity focus on evident clinical signs of systemic toxicity, including death, or organ-specific toxicity following acute and (sub)chronic exposure respectively. In toxicological and safety pharmacological studies with airborne test items targeting the airways or the lungs as a whole, lung function is a relevant endpoint for the characterization of potential adverse events (OECD, 2018a; Hoymann, 2012). Hence, the AO “decreased lung function” is relevant for regulatory decision-making in the context of (sub)chronic exposure (OECD, 2018b; OECD, 2018c).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Regulatory relevance of the AO “decreased lung function” is evident when looking at the increased risk of diseases in humans following inhalation exposure, and because of its links to other comorbidities and mortality.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">To aid diagnosis and monitoring of fibrosis, current recommendations include both the recording of potential environmental and occupational exposures as well as an assessment of lung function (Baumgartner et al., 2000). The latter typically confirms decreased lung function as demonstrated by a loss of lung volume. As the disease progresses, dyspnea and lung function worsen, and the prognosis is directly linked to the decline in FVC (Meltzer and Noble, 2008). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Segoe UI",sans-serif"><span style="color:black">Chronic exposure to cigarette smoke and other combustion-derived particles results in the development of COPD. COPD is diagnosed on the basis of spirometry results as laid out in the ATS/ERS Task Force documents on the standardization of lung function tests and their interpretation (Pellegrino et al., 2005; Culver et al., 2017, Graham et al., 2019). Rapid rates of decline in the lung function parameter FEV1 are linked to higher risk of exacerbations, increased hospitalization and early death (Wise et al., 2006; Celli, 2010). Reduced FEV1 also poses a risk for serious cardiovascular events and mortality associated with cardiovascular disease (Sin et al., 2005; Lee et al., 2015).</span></span></span></span></span></p>
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